Rheumatoid arthritis (RA) is a chronic inflammatory and destructive joint disease that affects 0.5–1.0% of the population in the industrialised world. RA is a polyarthritis and in the disease virtually all peripheral joints might be affected. Furthermore, extra-articular involvement is another hallmark of RA and this ranges from rheumatoid nodules to life threatening vasculitis. Although the cause of RA remains unknown, autoimmunity plays a pivotal role in its chronicity and progression (Breedveld, 1998). Many pathways involved in the generation of the disease have been recognised and some of these have been unequivocally identified as important by therapeutic proof of principle studies.
Management of RA is a major problem since there is no cure available. Drug therapy for RA rests on two principal approaches: symptomatic treatment with non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs). NSAIDs only interfere with a small segment of the inflammatory cascade (prostaglandin generation) but do not interfere with the underlying immuno-inflammatory events. By contrast, DMARDs modify the disease process in all these respects. DMARDs can be divided into small molecules and biological agents.
A number of biologicals have recently been approved for clinical treatment of RA. These drugs (proteins, e.g., monoclonal antibodies) prevent in general pro-inflammatory cytokines, in particular TNF-α and IL-1, from interacting with their receptors.
A number of small-molecule DMARDs are used today in RA therapy. In fact methotrexate is still the most commonly used DMARD and sulphasalazine was the second most common DMARD used in Europe during the 1990s. Thus, a number of drugs have been developed and used in RA therapy each targeting a specific pathway of importance to the generation of the disease.
The latest addition to the group of small chemical DMARDs is leflunomide (Merck Index 13th ed No. 5451).

Leflunomide is in vivo rapidly metabolised to the active metabolite A771726, which inhibits dihydroorotate-dehydrogenase (DHODH), an enzyme that is pivotally involved in de novo pyrimidine synthesis. Inhibition of this enzyme inhibits the growth of (pathologically) fast proliferating cells. The most important cell types for the immune response, the lymphocytes, use exclusively the synthesis of pyrimidines for their growth and react particularly to DHODH inhibition (Batt, 1999; Cherwinski et al., 1995). Substances that inhibit growth of lymphocytes are important medicaments for the treatment of autoimmune diseases including RA. The DHODH inhibiting leflunomide is the first medication of this class of compounds for the treatment of RA. The efficacy of leflunomide in the treatment of RA has been investigated in numerous Phase II and III clinical studies. Leflunomide has provided clinical proof of concept for the mechanism, but due to its side effects, e.g., liver abnormalities and influence on fertility, it is far from optimal for treatment of RA.
EP0497740 discloses benzyloxyphenyl derivatives of general formula (A)

Said patent concerns compounds possessing antihyperproliferative/antiinflammatory and anti-cancer activity. In a preferred group of compounds R1 and R3 are methoxy, and the benzyloxy moiety is in meta-position in respect to R6. R6 is carboxy or an ester group, R5 is hydroxy or acetylamino, especially hydroxy.
EP0815087 discloses trisubstituted phenyl derivatives of general formula (B)

Said patent concerns compounds for the treatment of inflammatory and proliferative skin diseases and cancer. The compounds are to be administered topically or in divided doses up to four times a day. In the most preferred compounds R1 and R2 are methoxy, W is CH2CH2, and R3 and R4 together with the phenyl ring form a condensed ring system.
Research Disclosure, 1998, 409(May), P561–P562 (No. 40953) discloses synthetic analogues of the natural product Javendustin A, of general formula (C)

Compounds are disclosed wherein R1 and R2 are the same or different and represent alkoxy, alkyl or alkenyloxy, R3 is i.a. alkoxy and R4 is i.a. acylamino.
Gennari et al., (1994) reported an anaerobic degradation in soil of 2-nitrophenoxy acids used as herbicides, e.g., acifluorfen, (Merck Index 13th ed. No. 111) that gives compound D.

There is no teaching in the literature disclosing the use of compound D as a pharmaceutical agent.
Symmetrical anthranilic acids of the general formula (E)
have been reported in the literature to be used, for example, as high temperature resistant polyheterocycles.
The synthesis of the anthranilic acid of formula (F)
has been reported by Sevbo et al. (1976). Compound F is used as a synthetic intermediate in the preparation of 2-amino-3-phenothiazone derivatives. There is no teaching in the literature disclosing the use of such intermediate as a pharmaceutical agent.